1. Field of the Invention
The present invention provides compounds, compositions, kits, and methods comprising botanical compounds and extracts for the prevention and treatment of inflammatory and metabolic disorders, in particular, insulin resistance syndromes, diabetes, obesity, weight gain, cardiovascular disease and cancer. More specifically, the invention relates to anti-inflammatory, pharmaceutical compositions and therapeutic methods utilizing such compositions to modify adipocyte physiology to enhance insulin sensitivity.
2. Description of the Related Art
Research has implicated dysregulated inflammatory processes in the pathogenesis of many prevalent, chronic diseases including metabolic syndrome, insulin resistance, diabetes, obesity, dyslipidemia, lipodystrophy and cardiovascular disease. Increased plasma concentrations of tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), C-reactive protein (CRP) and plasminogen activator inhibitor-1 (PAI-1), which are characteristic of chronic inflammation, are found in varying degrees in all of these pathologies [Dandona, P., et al. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25(1):407, (2004); Dandona, P. Endothelium, inflammation, and diabetes. Curr Diab Rep 2(4):311-315, (2002)]. As such anti-inflammatory directed treatment modalities have the potential to provide therapeutic or palliative benefits for these conditions.
Insulin resistance is now well recognized as a chronic inflammatory state. The interrelationship between inflammation and inflammatory mediators and the diabetic state, whether diabetes type 1 or type 2, has long been noted. For example, insulin dependent diabetes mellitus (IDDM) is characterized by an initial inflammatory response or cellular infiltration in or around the pancreatic islet cells [Gepts, W. Pathologic anatomy of the pancreas in juvenile diabetes mellitus. Diabetes 14: 619-633, (1965); see also Koliopanos, A., et al., Cyclooxygenase 2 expression in chronic pancreatitis: Correlation with stage of the disease and diabetes mellitus. Digestion 64: 240-247, (2001); and Luo, C., et al., Cellular distribution and contribution of cyclooxygenase (COX)-2 to diabetogenesis in NOD mouse. Cell Tissue Res. 310: 169-175, (2002)].
Additionally, Helmersson, et al., demonstrated that type 2 diabetes in elderly men is related to COX-mediated inflammation, as reflected by enhanced prostaglandin formation. The high levels of cytokine-mediated acute-phase proteins observed in men with diabetes appear to be related to obesity and increased fasting insulin. These results reflect the current understanding that the appearance of chronic inflammation is an early process in the pathogenesis of diabetes [Helmersson, J., et al. Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population. Circulation 109: 1729-1734, (2004)].
The cyclooxygenase enzymes, which catalyze a critical step in the conversion of arachadonic acid to prostaglandins, are also recognized as important mediators of both acute and chronic inflammation. For example, cyclooxygenase (COX)-2 is overexpressed in chronic pancreatitis, which may play a role in the progression of the disease [Schlosser, W., et al., Cyclooxygenase-2 is overexpressed in chronic pancreatitis. Pancreas 25(1): 26-30, (2002)]. Further, COX-2 inhibition has been shown to prevent IDDM in streptozotocin treated mice [Tabatabai, T., et al., COX-2 inhibition prevents insulin-dependent diabetes in low-dose streptozotocin treated mice. Biochem. And Biophys. Res. Comm. 273: 699-704, (2000)] and in conjunction with other cytokines, such as, for example IL-1β, TNF-α, and IFN-γ, to play a role in cytokine induced β-cell dysfunction in islet inflammation and diabetes [Heitmeier, M. R., et al., Role of cyclooxygenase-2 in cytokine-induced β-cell dysfunction and damage by isolated rat and human islets. J. Bio. Chem. 279(51): 53145-53151, (2004); and McDaniel, M. L., et al., Cytokines and nitric oxide in islet inflammation and diabetes. Proc. Soc. Exp. Biol. Med. 211: 24-32, (1996)].
Corbett and co-workers demonstrated that tyrosine kinase inhibitors prevent IL-1β, TNF-α, and IFN-γ induction of the expression of iNOS and COX-2 by human islet cells and further suggest that the cytokines released during islet inflammation may participate in β-cell destruction in IDDM [Corbett, J. A., et al., Tyrosine kinase inhibitors prevent cytokine-induced expression of iNOS and COX-2 by human islets. Am J. Physiol. 270(6 Pt 1):C1581-7, (June 1996)]. Insofar as IL-1β, TNF-α, and IFN-γ are under NF-κB control, modalities which regulate NF-κB expression may be expected to have a beneficial effect on diabetes through the regulation of iNOS and COX-2 expression and activity. For a review of inflammations and diabetes see Tak, P. P. and Firestein, G. S. INF-κB: a key role in inflammatory diseases. J. Clin. Invest. 107:7-11, (2001) or Yuan, M., et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Iκκβ. Science 293: 1673-1677, (2001)].
As previously noted, COX enzymes play a critical role in arachadonic metabolism and prostaglandin synthesis and it has long been known that drugs which inhibit prostaglandin synthesis can improve glucose disposal. Robertson and co-workers have demonstrated a) an in vivo inhibition of insulin secretion by prostaglandin E1, b) a role for prostaglandin E2 in defective insulin secretion and carbohydrate intolerance in diabetes mellitus, and c) that COX-2 is dominant in pancreatic islet prostaglandin synthesis. [Robertson, R. P., et al., Inhibition of in vivo insulin secretion by prostaglandin E1. J. Clin. Invest. 54: 310-315, (1974); Robertson, R. P. and Chen, M. A role for prostaglandin E in defective insulin secretion and carbohydrate intolerance in diabetes mellitus. J. Clin. Invest. 60: 747-753, (1977); and Robertson, R. P. Dominance of cyclooxygenase-2 in the regulation of pancreatic islet prostaglandin synthesis. Diabetes 47: 1379-1383, (1998)]. Additionally, Litherland and co-workers have shown that an antigen presenting T-cell defect in IDDM is defined by aberrant prostaglandin synthase 2 expression [Litherland, S. A., et al., Aberrant prostaglandin synthase 2 expression defines an antigen-presenting cell defect for insulin-dependent diabetes mellitus. J. Clin. Invest. 104: 515-523, (1999)].
Hyperinsulinemia and insulin action were initially proposed as common preceding factors of hypertension, low HDL cholesterol, hypertriglyceridemia, abdominal obesity and altered glucose tolerance, further linking these abnormalities to the development of coronary heart disease in the late 1990s.
The concept of inflammation and adipocyte interaction in relation to these metabolic conditions started with a seminal publication by Hotamisligil et al. in 1993, which demonstrated that adipocytes constitutively express the pro-inflammatory cytokine tumor necrosis factor-α (TNFα), and that TNFα expression in the adipocytes of obese animals (ob/ob mouse, db/db mouse and fa/fa Zucker rat) is markedly increased. Further, neutralization of TNFα by soluble TNFα receptor leads to a decrease in insulin resistance in these animals [Hotamisligil G. S., et al. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259:87-91, (1993)]. These observations provide a link between an increase in the expression and plasma concentration of a pro-inflammatory cytokine and insulin resistance.
Clinical and experimental data developed since 1993 suggest that all major components of the metabolic syndrome including insulin insensitivity and obesity are associated with inflammatory conditions characterized by increased plasma concentrations of pro-inflammatory cytokines such as TNFα, Interleukin-6 (IL-6), C-reactive protein (CRP) and plasminogen activator inhibitor-1 (PAI-1) [Yudkin, J. S., et al. C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler. Thromb. Vasc. Biol. 19:972-978, (1999); Mohamed-Ali, V., et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-a, in vivo. Endocrinol. Metab. 82:4196-4200, (1997); Lundgren, C. H., et al. Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease. Circulation 93:106-110, (1996)]. Clinically, it has been shown that human adipose tissue expresses TNFα constitutively and that expression falls after weight loss [Kern, P. A., et al. The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J. Clin. Invest. 95:2111-2119, (1995)].
The prevalence of diabetes mellitus has increased roughly in parallel with that of obesity, which has itself doubled in the United States in the last twenty years. Some experts have stated that obesity in the United States is an epidemic. In any case, as the population ages, it is likely that the rate of obesity will increase with time. The correlation between obesity and diabetes is manifest, as are the correlations between cardiovascular disease and both obesity and diabetes. A non-obese, type two diabetic is far more likely to suffer from cardiovascular disease than is a non-obese, non-diabetic; and an obese non-diabetic is at an even higher risk for cardiovascular disease than is a non-obese diabetic. Thus, in addition to inflammation, there are apparently causal links between cardiovascular disease and both obesity and diabetes.
It is now generally accepted that adipose tissue acts as an endocrine organ producing a number of biologically active peptides with an important role in the regulation of food intake, energy expenditure and a series of metabolic processes. Adipose tissue secretes a number of bioactive peptides collectively termed adipokines. Through their secretory function, adipocytes lie at the heart of a complex network capable of influencing several physiological processes (FIG. 1). Dysregulation of adipokine production with alteration of adipocyte mass has been implicated in metabolic and cardiovascular complications of obesity. In obese individuals, excessive production of acylation-stimulating protein (ASP), TNFα, IL-6 or resistin deteriorates insulin action in muscles and liver, while increased angiotensinogen and PAI-1 secretion favors hypertension and impaired fibrinolysis. Leptin regulates energy balance and exerts an insulin-sensitizing effect. These beneficial effects are reduced in obesity due to leptin resistance. Adiponectin increases insulin action in muscles and liver and exerts an anti-atherogenic effect. Further, adiponectin is the only known adipokine whose circulating levels are decreased in the obese state. The thiazolidinedione anti-diabetic drugs increase plasma adiponectin, supporting the idea that adipokine-targeted pharmacology represents a promising therapeutic approach to control non-insulin dependent diabetes mellitus (NIDDM), diabetes and cardiovascular diseases in obesity (FIG. 2) [Guerre-Millo, M. Adipose tissue and adipokines: for better or worse. Diabetes Metabolism 30:13-19, (2004)].
Insulin resistance and/or hyperinsulinemia have been postulated to be the cause of the other abnormal metabolic and cardiovascular risk factors that occur in the metabolic syndrome (FIG. 3). These risk factors have been identified as (1) central obesity (including increased visceral fat); (2) a characteristic dyslipidemia that includes an elevated plasma triglyceride, a low plasma high-density lipoprotein (HDL), and a small dense low-density lipoprotein (LDL) cholesterol particle pattern; (3) a procoagulant state made up of elevated plasma fibrinogen and plasminogen activator inhibitor-1; (4) elevated systolic and diastolic blood pressure; (5) hyperuricemia; and (6) microalbuminuria [Lebovitz, H. E., and Banerji, M. A. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res. 56:265-94, (2001)].
One method for the treatment of insulin resistance is through the use of oral antihyperglycemic agents. Oral antihyperglycemic agents can be classified into six, distinct classes based upon mechanism of action: (1) biguanides, such as metformin, that decrease hepatic glucose production; (2) sulfonylureas such as glipizide, glyburide, and glimepiride, and (3) nonsulfonylureas such as repaglinide and nateglinide that increase pancreatic insulin secretion; (4) α-glucosidase inhibitors, with acarbose being the only representative on the market, that delay intestinal carbohydrate absorption; (5) thiazolidinediones, rosiglitazone and pioglitazone, agents that increase fatty acid uptake of adipocytes as well as glucose uptake in both muscle and fat; and 6) anti-inflammatories (e.g. aspirin (not used due to toxicity associated with the levels necessary to improve glucose control)) [Scheen, A. J. Drug treatment of non-insulin-dependent diabetes mellitus in the 1990s. Achievements and future developments. Drugs 54(3):355-368, (September 1997); Scheen, A. J. and Lefebvre, P. J. Antihyperglycaemic agents. Drug interactions of clinical importance. Drug Saf; 12(1):32-45, (January 1995); Inzucchi, S. E. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA. 287(3):360-372, (Jan. 16, 2002); and Gao, Z., et al. Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J. Bio. Chem. 278(27): 24944-24950, (2003)].
With few exceptions, the available antidiabetic drugs are equally effective at lowering glucose concentrations. Due to their differing mechanisms of action, they appear to have distinct metabolic effects as reflected in their effect on cardiovascular risk and adverse effect profiles. Metformin currently is the only drug associated with weight loss (or no effect on body weight); it has become the most widely prescribed single hyperglycemic drug and is generally regarded as the best first-line agent especially in the obese patient without contraindications for its use.
Failure to maintain adequate blood glucose for extended periods of time, however, is frequently seen independent of choice of drug. For example, sulphonylureas have a secondary failure rate of up to 10% each year. This associated worsening hyperglycemia often necessitates the use of polypharmacy; i.e. three years after diagnosis, approximately half of patients require more than one pharmaceutical agent and within nine years this increases to 75% of all patients [Turner, R. C., Cull, C. A., Frighi, V., and Holman, R. R. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 281(21):2005-2012, (Jun. 2, 1999)]. Moreover, despite the use of combination therapy physicians generally do not reach targets for glycemic control [Zinman, B. PPARgamma agonists in type 2 diabetes: how far have we come in preventing the inevitable’? A review of the metabolic effects of rosiglitazone. Diabetes Obes Metab. 3 Suppl 1:34-43, (August 2001)].
Statistics on the increasing incidence of NIDDM and the rate of therapeutic failures in maintaining adequate blood glucose indicate that new approaches in the treatment of NIDDM and its complications are important public health priorities. Although diet, regular exercise and weight control have proven effective for modifying the pathogenesis of insulin resistance and increasing the efficacy of antidiabetic drugs, it can be anticipated that a majority of persons will eschew dietary modifications and exercise and that monotherapy will ultimately fail to adequately control the myriad of metabolic imbalances manifest in NIDDM. In light of the tremendous cost of NIDDM, both in terms of human suffering and monetary resources, it seems highly desirable to have additional agents to support treatment [McCarty, M. F. Nutraceutical resources for diabetes prevention—an update. Med. Hypotheses. 64(1):151-158, (2005); McCarty, M. F. Toward practical prevention of type 2 diabetes. Med Hypotheses. 54(5):786-793, (May 2000)].
In addition to diabetes, obesity and cardiovascular disease, other conditions are now recognized as inflammatory pathologies. These include (1) diseases of the digestive organs such as ulcerative colitis, Crohn's disease, pancreatitis and gastritis; (2) proliferative diseases, such as benign tumors, polyps, hereditary polyposis syndrome, colon cancer, rectal cancer, breast cancer, prostate cancer, and stomach cancer; and (3) ulcerous disease of the digestive organs, and (4) cardiovascular pathologies including stenocardia, atherosclerosis, myocardial infarction, sequelae of stenocardia or myocardial infarction, senile dementia, and cerebrovascular diseases. Thus, it is to be expected that effective anti-inflammatory based methods of improving insulin sensitivity will be useful in the treatment, prevention or delay of onset of one or more of the foregoing inflammatory disorders. Botanical based anti-inflammatory compounds and extracts represent an as yet underutilized source for palliative or preventive treatment modalities.
Folk and herbal medicine, such as for example, Ayurvedic medicine, have ascribed many healing properties to, and resulting from, the use of numerous and varied botanical compounds and extracts. Current research has demonstrated that many of these claims are based on more than a factual grain of truth. Two such botanical sources are hops (members of the genus Humulus) and acacia (members of the botanical genus Acacia).
Hops, long known to the brewers' art for providing the bitter taste to beers, have had many health benefits ascribed to its use. Such benefits include antioxidant activity, anti-inflammatory effects, anticarcinogenic activity, etc. See, for example, Gerhauser, C. Beer constituents as potential cancer chemopreventative agents. Eur. J. of Cancer, 41(13):1941-54, (2005).
Acacia is a genus of leguminous trees and shrubs. The genus Acacia includes more than 1000 species belonging to the family Leguminosae and subfamily Mimosoideae. Acacias are distributed worldwide in tropical and subtropical areas of central and South America, Africa, parts of Asia, as well as Australia (which has the largest number of endemic species). Acacias occur primarily in dry and arid regions, where the forests are often in the nature of open thorny shrubs.
Acacia catechu is believed to have antiseptic and astringent qualities. Preparations are usually in the form of an alcohol solution (tincture), which can be taken internally, used in a mouthwash, or painted directly onto inflamed tissues in the mouth. Traditional medicine supports its oral use for the following indications: sore throat, gingivitis, colitis, diarrhea, bleeding, diabetes, skin diseases, cancer, toothaches and inflammation in the mouth. Singh, [Singh, K. N., et al., Hypoglycaemic activity of Acacia catechu, Acacia suma, and Albizzia odoratissima seed diets in normal albino rats. Ind. J. Med. Res 64: 754-757, (1976)] discloses that a diet of seeds from these Acacia plants had hypoglycemic activity in normal rats but not in alloxan induced diabetic rats. Singh however neither teaches nor addresses whether portions of the plants other than the seed meat, for example bark or heartwood, or plant material extracts have any hypoglycemic activity in either normal or diabetic subjects.
Catechu is used orally in some parts of the world as an anti-fertility drug. Topically, catechu is used for skin diseases, hemorrhoids, traumatic injuries, to stop bleeding and for dressing wounds. Catechu has been included in mouthwashes and gargles for gingivitis, stomatitis, pharyngitis, and oral ulcers. In foods and beverages, it is used as a flavoring agent. However, Acacia catechu is not well researched and little is known regarding the full spectrum or identification of potentially pharmaceutically active compounds.
Aqueous infusions of the seed pods or bark of Acacia nilotica have been used in folk medicine for gastrointestinal disorders while pulverized seeds and pods have been applied to sores of the mouth or to hasten cicatrisation of syphilitic ulcers [Amos, S., The pharmacological effects of an aqueous extract from Acacia nilotica seeds. Phytother. Res. 13: 683-685, (1999), and Al-Mustafa, Z. H. and Dafallah, A. A. A study on the toxicology of Acacia nilotica. Am. J. Clin. Med. 28(1): 23-29, (2000)]. Nor are Acacia species the only botanicals purportedly to have antidiabetic properties.
Another botanical, Momordica charantia (bitter melon), is used primarily as an alternative therapy for diabetes. A member of the Curcurbitaceae family, the plant grows in tropical areas, including parts of the Amazon Basin, Africa, Asia, the Caribbean, and South America. Bitter melon has a long history of use as a hypoglycemic agent in Asia, Africa, and Latin America, where the plant extract has been referred to as vegetable insulin. Other botanicals of interest include African cucumber, balsam-apple, balsambirne, balsam pear, balsamo, betamomorcharin, bitter apple, bitter cucumber, bitter gourd, bittergurke, carilla gourd, charantin, chinli-chih, cundeamor, kakara, kuguazi, k'u-kua, lai margose. Four clinical trials have found bitter melon juice, fruit, and dried powder to have a moderate hypoglycemic effect. Data from in vitro, animal and several human studies do suggest that bitter melon and some of its crude extracts have a moderate hypoglycemic effect. These clinical studies, however, were small and were not randomized or double-blinded. Reported adverse effects of bitter melon include hypoglycemic coma and convulsions in children, reduced fertility in mice, a favism-like syndrome, increases in γ-glutamyltransferase and alkaline phosphatase levels in animals, and headaches [Basch, E., et al. Bitter melon (Momordica chanantia): A review of efficacy and safety. Am J Health-Syst Pharm 60:356-359, (2003)]. Thus, compositions or methods to increase the clinical efficacy of bitter melon while decreasing the dose would be useful for the treatment of type 2 diabetes or metabolic syndrome.
Aloe vera has been promoted for a large variety of medical conditions ranging from burns to constipation. Published work in animals combined with the limited clinical research suggests that oral administration of aloe vera might be a useful adjunct for lowering blood glucose in diabetic patients as well as for reducing blood lipid levels in patients with hyperlipidemia [Eshun, K. Aloe vera: a valuable ingredient for the food, pharmaceutical and cosmetic industries—a review. Crit Rev Food Sci Nutr. 44(2):91-96, (2004).]. However, clinical effectiveness of oral or topical aloe vera is not sufficiently defined at present. Ultimately, the most effective use of aloe vera in diabetes or metabolic syndrome may be in combination with other materials.
Germacrene A and Germacrene D are sesquiterpenes found in a wide variety of plants and exhibit anti-ulcer, anti-inflammatory, anti-fungal and anti-bacterial activity. To date no research has demonstrated that these compounds exhibit hypoglycemic or insulin sensitizing properties.
Red raspberry seed oil (Rubus idaeus) is an excellent dietary source of potent antioxidants, including gamma-tocopherol, the most active form of Vitamin E plus linoleic, linolenic and palmitic acids. Limited in vitro research has demonstrated that it possesses anti-inflammatory properties. The natural tocopherol content of red raspberry seed oil is very high, which may aid in the prevention of oxidative stress.
Wasabi (Wasabi japonica) is used as a spice in daily foodstuffs. Allylisothiocyanate (AIT) is a potent component of wasabi and is formed by plant enzymes following preparation by grating. It is known that AIT shows inhibitory effects on the growth of food poisoning bacteria and fungi. Several functional properties of roots and leaves from wasabi have been examined in vitro. Wasabi has shown peroxidase activity and has also exhibited antioxidative and superoxide scavenging potency. The antimutagenic activity of wasabi was observed toward 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, a well-known mutagen/carcinogen in broiled fish and meat. It also decreased His+ revertant colonies of 3-chloro-4-dichloromethyl-5-hydroxy-2(5H)-furanone (MX) in the Ames test with (−)-(R)-7-methylsulfinylheptyl isothiocyanate identified as the anti-mutagen. These data suggest that wasabi might be a potent functional food source for maintaining human health.
Davana oil is obtained from the air-dried, aerial parts of Artemisia pallens. The herb grows in the same parts of southern India where sandalwood is grown. Its odor is sharp, penetrating, bitter-green, foliage like and powerfully herbaceous with a sweet balsamic, tenacious undertone. While used primarily in the perfume industry, the essential oil possesses antibacterial and antifungal properties. The oil contains a variety of terpenoids and the germacranolides 4,5β-epoxy-10α-hydroxy-1-en-3-one-trans-germacran-6α,12-olide and 4,5β-Epoxy-10α-hydroxy-1-en-3-one-trans-germacran-6α,12-olide [Pujar, P. P., et al. A new germacranolide from Artemisia pallens Fitoterapia 71:590-592, (2000)].
Bacopa monniera (BM), a traditional Ayurvedic medicine, has been used for centuries as a memory enhancing, anti-inflammatory, analgesic, antipyretic, sedative and antiepileptic agent. The plant, plant extracts and isolated bacosideA3 (3beta,16beta,23R)-16,23:16,30-Diepoxy-20-hydroxydammar-24-en-3-yl O-alpha-L-arabinofuranosyl-(1-2)-O-(beta-D-glucopyranosyl-(1-3))-beta-D-glucopyranoside), the major active principle, have been investigated for their neuropharmacological effects and a number of reports are available ascribing their nootropic action. In addition, researchers have evaluated the anti-inflammatory, cardiotonic and other pharmacological effects of BM preparations/extracts.
Oleoresin Fennel is a volatile oil distilled from fennel (the seeds of Foeniculum vulgare), used as a flavoring agent for pharmaceuticals and formerly as a carminative. The best varieties of fennel yield from 4 to 5 percent of volatile oil (sp. gr. 0.960 to 0.930), the principal constituents of which are anethol (1-methoxy-4-propenylbenzene, 50 to 60 percent) and fenchone (1,3,3-trimethyl-2-norcamphanone, 18 to 22 percent). Fenchone is a colorless liquid possessing a pungent, camphoraceous odor and taste, and when present gives the disagreeable bitter taste to many of the commercial oils. It has been postulated that this contributes materially to the medicinal properties of the oil, hence only such varieties of fennel as contain a good proportion of fenchone are suitable for medicinal use. There are also present in oil of fennel, d-pinene, phellandrine, anisic acid and anisic aldehyde. Limonene is also at times present as a constituent.
Centella asiatica, is a botanical that has wound healing and anti-aging properties. Asiaticoside (2alpha,3beta,23-Trihydroxy-urs-12-en-28-saeure(O-alpha-L-rhamnopyranosyl-(1-4)-O-beta-D-glucopyranosyl-(1-6)-O-beta-D-glucopyranosyl)ester) has been derived from the plant Centella asiatica and is known to possess wound healing activity where the enhanced healing activity has been attributed to increased collagen formation and angiogenesis.
For thousands of years the beneficial properties of the neem tree (Azadirachta indica) have been recognized in India, and it is perhaps the country's most useful traditional plant. Neem has been “universally” accepted as a wonder tree because of its diverse utility. Over 700 herbal preparations based on neem are found in Ayurveda, Siddha, Unani, Amchi and other local health traditions; over 160 local practices are known in different parts of the country in which neem forms an important or sole ingredient in curing or treating various human ailments or disorders. Aqueous leaf extracts have been shown to reduce hyperglycemia in streptozotocin-induced diabetes, and this effect is possibly due to the presence of a flavonoid, quercetin. A leaf extract of A. indica has also been reported to block the effects of epinephrine on glucose metabolism and reduce peripheral glucose utilization in diabetic rats, and to some extent in normal rats; this indicates the antihyperglycemic potential of the plant. The hypoglycemic effects of neem-leaf extract and seed oil in normal and alloxan-induced diabetic rabbits has also been reported. The effect, however, was more pronounced in diabetic animals where administration for four weeks after alloxan-induced diabetes significantly reduced blood glucose levels. The hypoglycemic effect was found to be comparable to that of the sulfonylurea glibenclamide. Pretreatment with an A. indica leaf extract or seed oil administration started two weeks prior to alloxan partially prevented the rise in blood glucose levels relative to control diabetic animals. The results suggest that A. indica could be of benefit in diabetes mellitus for controlling the blood sugar or may also be helpful in preventing or delaying the onset of the disease [reviewed in Brahmachari, G. Neem—an omnipotent plant: a retrospection. Chembiochem. 5(4):408-421, (Apr. 2, 2004)]. However, since neem contains a plethora of phytochemicals with unknown effects with chronic administration, it would be beneficial to reduce the dose of neem through the combination with a well-defined material.
A yellow, pigmented fraction isolated from the rhizomes of Curcuma longa contains curcuminoids belonging to the dicinnamoyl methane group. Curcuminoids are present to the extent of 3 to 5 percent. They are considered the most important active ingredients and are believed to be responsible for the biological activity of Curcuma longa. Though their major activity is anti-inflammatory, curcuminoids have been reported to possess antioxidant, anti-allergic, wound healing, antispasmodic, antibacterial, antifungal and antitumor activity as well. Curcumin was isolated in 1815 and structurally defined in 1910. Other curcuminoids isolated from Curcum longa include demethoxycurcumin, bisdemethoxycurcumin, a cis-trans geometrical isomer of curcumin, and cyclocurcumin. Curcuminoids may be found in other botanicals in addition to Curcuma longa, such as Curcuma xanthorrhiza and Curcuma zedoaria. 
Curcuminoids are well known for their anti-inflammatory activity. Tumeric is one of the oldest anti-inflammatory drugs used in Ayurvedic medicine. The anti-inflammatory activity of curcuminoids has been evaluated in inflammatory reaction models such as chemical or physical irritants like carrageenin, cotton pellets, formaldehyde and the granuloma pouch. A Curcuma longa rhizome ethanol extract significantly suppressed an increase in blood glucose level in type 2 diabetic KK-A(y) mice. In an in vitro evaluation, the extract stimulated human adipocyte differentiation in a dose-dependent manner and showed human peroxisome proliferator-activated receptor (PPAR)-gamma ligand-binding activity in a GAL4-PPAR-gamma chimera assay. The main constituents of the extract were identified as curcumin, demethoxycurcumin, bisdemethoxycurcumin, and ar-turmerone, which had also PPAR-gamma ligand-binding activity [Kuroda, M., Mimaki, Y., et al. Hypoglycemic effects of turmeric (Curcuma longa L. Rhizomes) on genetically diabetic KK-Ay mice. Biol Pharm Bull 28(5): 937-939, (2005)].
However, chronic dosing of curcuminoids may cause stomach distress and irritation due to the fact that curcuminoids act on prostaglandin production in a manner similar to that of aspirin and aspirin-like anti-inflammatory agents. Thus, it would be desirable to reduce the dose of curcuminoids by having a combination of curcuminoids with other hypoglycemic agents that function synergistically to increase insulin activity.
Conjugated linoleic acid (CLA) is a nonessential fatty acid consisting of approximately 20 closely related fatty acid isomers. CLA refers to a group of polyunsaturated fatty acids that exist as positional and stero-isomers of conjugated dienoic octadecadienoate (18:2). CLA comes in two isomers, the 9,11 isomer which appears responsible for improving muscle growth and the 10,12 isomer which primarily prevents lipogenesis (storage of fat in adipose tissue). Most supplements sold in stores contain a 50/50 mix of both isomers.
Various antioxidant and antitumor properties have been attributed to CLA, however it is suspected that an anti-inflammatory concentration within human tissues may not be attainable via oral consumption. Many studies on CLA in humans include the tendency for reduced body fat, particularly abdominal fat, changes in serum total lipids and decreased whole body glucose uptake. Dietary CLA supplementation shows to be safe and does not seem to have any adverse effects. The maximum response to reduce body fat mass was achieved with a 3.4 g daily dose. Some studies in humans, however, have demonstrated a decrease in insulin sensitivity resulting from high does of CLA. It would be desirable to have combinations of CLA that do not decrease insulin action. Further, it would also be desirable to have combinations of CLA that could extend the usefulness of CLA to other chronic inflammatory diseases such as osteoporosis.
Despite advances in treating diabetes mellitus in recent years, there remains a need for compositions for treatment and prevention of diabetes and diabetes-related conditions and disorders, such as insulin resistance and metabolic syndrome X. With the aforementioned increase in the incidence of obesity, compositions and methods for treatment and prevention of obesity are also needed. There is also a need for effective compositions and methods for preventing and treating cardiovascular disease, including prevention and treatment of atherosclerosis. Additionally, given the identification of multiple conditions that can be envisioned as primarily inflammatory conditions, there is a need for compositions and methods useful in the treatment and prevention of inflammation related to a number of disorders. Finally, there is a pressing need to identify compounds which, in addition to their own activity, can augment, synergize, or otherwise extend the efficacy of current first line treatment modalities for diabetes and diabetes related conditions and disorders. The present invention satisfies these needs and provides related advantages as well.